1. Field of the Invention
The invention relates generally to polypeptide antibiotics produced by bacteria isolated from marine environments. In particular, the present invention is directed to antibacterial compositions useful for treating a broad spectrum of bacterial infections.
2. Description of Background Art
The search for new and advanced cancer treatments is dependent upon the discovery of new compounds, the development of new therapeutic strategies and advances in predictive models for disease. Due to the immense technical advances that have been made in the pharmaceutical industry and medicine, there is a resurging interest in the use of natural products in the formulation of therapeutic drugs. In fact, many of the drugs in use today are derivatives of natural products, which provide additional incentive to take further advantage of the biodiversity available for the discovery of new drugs, particularly in the area of cancer therapy.
In response to evolutionary pressures imposed over time, new molecules and compounds constantly evolve, resulting in a structural diversity against which modern technologies such as combinatorial chemistry cannot compete. To make use of the biological and chemical diversity of natural products, it has become increasingly clear that the most powerful approach in the search for new drugs begins with drug leads revealed by natural product-based drug discovery techniques, and subsequently utilizing genomic-based platforms to identify and produce the lead compounds that are the basis for next generation drugs.
Since the discovery of penicillin in 1929, nearly 50,000 natural products have been isolated from microorganisms. Over 10,000 of these compounds have been shown to have biological activity and 100 of these are in use today in the treatment of a wide range of human and animal diseases. Numerous antibiotics and anticancer agents have been identified and have provided a powerful weapon in the arsenal of drugs for treating infectious diseases.
Microbes, unfortunately, constantly adapt to changing environments so that multiple drug resistance develops rapidly after infectious microorganisms are exposed to new antimicrobial agents. This resistance poses a continuing challenge to identify new agents that will effectively control bacterial growth and propagation.
A majority of antibiotics have, like penicillin, been isolated from natural sources or derived from bioactive natural products. The list is extensive and includes β-lactam antibiotics such as the cephalosporin family, chloramphenicol, vancomycin, bacitracin and structurally diverse compounds such as brominated pyrroles, magnesidins, and substituted biphenyldiols. The sources of these compounds are equally diverse and range from soil bacteria to marine pseudomonads and bioflora.
The oceans of the world cover over 70% of the earth's surface and have been described as being the “mother of the origin of life.” Given the uniqueness of the environment found in the oceans at various geographic locations around the world, organisms have responded by developing the structurally unique natural compounds required for adaptation and survival in a marine environment. Many of these compounds show pharmacologic activity against many human illnesses, ranging from infectious diseases to cancers. Previously discovered life saving drugs and potentially new drugs have been and are being isolated from microorganisms, algae, plants and invertebrates. With the advent of the technological advances made in the biotechnology, biomedical and pharmaceutical arenas, the discovery of new therapeutics from aquatic organisms has become a “new science”. Of the 25,000 plant species classified to date, only 10% have been studied in attempts to discover new therapeutically active compounds.
Marine environments have been even less utilized as sources of new drugs. Over 80% of the world's plant and animal species are found in a marine environment. Of the 34 fundamental phyla representing life, 17 occur on land whereas 32 occur in the ocean. As of 2004, basic research has led to the isolation of approximately 14,000 marine natural products with approximately 10-15 different natural products entering clinical testing (FDA sponsored clinical trials) in the cancer, infectious disease, pain and inflammatory disease fields
Despite recognition that the marine environment is an exceptional reservoir of bioactive natural products arising from an amazing diversity of life, the identification of potential new drugs from the oceans has progressed only slowly. Bioactive compounds have been extracted from a variety of marine organisms: tunicates, sponges, soft corals, sea hares, nudibranchs, bryozoans, sea slugs and microorganisms. Spongouridine and spongothymidine from the Caribbean sponge were among the first bioactive compounds isolated over fifty years ago.
Drug research studies on sponge-derived products has led to the development of anticancer and antiviral compounds. Two successfully launched marine organism-derived (or analog derived) products reaching the clinics within the last 30 years are Acyclovir (synthetically known as Ara A) and cephalosporin. Synthetic Ara A was modeled on the previously isolated sponge-derived spongothymidine or spongouridine and later isolated as a natural product from Eunicella cavolini. The antibiotic mimosamycin was isolated from a nudibranch sea slug and also found in certain sponges.
Secondary metabolites of marine organisms have also been studied over the past decades, which have often exhibited unique structures. Between 2000 and 2005, ziconotide, aplidine, KRN7000, discodermolide, bryostatin, synthadotin, dolastatin 10, soblidotin, halichondrin, HTI-286, kahalalide F, spisulosine, squalamine and ecteinascidin 743 have been identified from marine sources as potential drug candidates (Butler, 2005; Newman and Cragg, 2004A; Newman and Cragg, 2004B.) Several of these compounds are or have been in clinical trials.
Ziconotide, a 24-27 amino acid peptide from the -conotoxin cyclic cysteine known family, was identified from cone snail (Conus magnus) venom. It is a novel non-opioid analgesic that blocks the N-type voltage gated channel and was developed for management of severe chronic pain.
Aplidine is an analog of the didemnins isolated from Aplidium albicans, a Mediterranean tunicate, and is reported to show activity against medullary thyroid carcinoma, renal carcinoma, melanoma and tumors of neuroendocrine origin and to inhibit secretion of vascular endothelial growth factor (VEGF) (Taraboletti, 2004).
Agelasphins are new glycosphingolipids isolated as antitumor agents from Agelas mauritianus, an Okinawan sponge. KRN7000 is a synthetic derivative in clinical trials whose activity is attributed to natural killer cell activation effected as a ligand of VαT cell antigen receptor (Hayakawa, et al., 2003).
Bryostatin was isolated from Bulgula neritina and binds to the same receptors as phobol esters but differs in not having any tumor promoting activity. Binding of bryostatin downregulates protein kinase C isoforms in several tumor cells, causing inhibition of growth, alteration of differentiation and/or cell death (Newman, 2005).
Discodermolide has been isolated from Discodermia dissolute and found to inhibit tumor cell growth in vitro (Capon, 2001) as do dolastatins, which are linear peptides isolated from the Indian Ocean sea hare Dolabela auricularia (Pettit, et al., 1989).
Other potential drugs have been isolated from marine sources, some of which are in or are candidates for clinical trial studies. Table 1 is a list of examples of additional compounds recovered from marine environments and the organism from which it was isolated.
TABLE 1DRUGSOURCEORGANISMHalichondrinHalichondria okadaiE7389HTI-286spongeHemiasterella minorKahalalide FmolluskElysia rufescensSpisulosineSpisula polynymaSqualaminedogfish sharkSqualus acanthiasEcteinascidinmarine tunicateEcteinascidia turbinate
The vast majority of compounds currently in clinical trials or being considered as potential drug candidates exhibit antitumor activity, although the search for other classes of drugs has currently produced far fewer candidates.
Marine microorganisms have produced several potential antimicrobials, and new antibiotics isolated over the past several years, include lololatin, agrochelin (Acebal, et al., 1999) and sesbanimides from agrobacterium, pelagiomicins from Pelagiobacter variabilis, d-indomycinone from a Streptomyces sp. (Biabini, et al., 1997) and dihydrophencomycin from Streptomyces (Pusecker, et al., 1997). Pseudoalteromonas Alteromonas has also been reported to produce antibiotics and other bioactive substances (Gauthier, et al., 1995).
Marine sources historically have been underutilized in the search for new drugs and are only now being more fully exploited by interdisciplinary groups devoted solely to drug discovery research. Despite some progress in identifying new antimicrobial compounds, there are a limited number of marine-derived compounds that are active against MDR bacteria. In 2005, only 6 new anti-bacterial pharmaceuticals were reported to be in the development pipeline (Usdin, 2006).
Recently, an unusual pair of antibiotics isolated from bacteria obtained from ocean sediments have been identified by Fenical, et al. (2008). The new compounds have a basic pyrrole structure that is an N, C2-linked bispyrrole, and exhibit antimicrobial activity against methicillin-resistant S. aureus. 
The rapid increase in the number of MDR strains and the decreasing effectiveness of currently used antimicrobials, are strong indications of the need for new and effective first-generation antibiotics.